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. 1998;78(Suppl 3):35–40. doi: 10.1038/bjc.1998.752

Clinical studies with MTA.

A H Calvert 1, J M Walling 1
PMCID: PMC2062802  PMID: 9717989

Abstract

MTA (LY231514), a multi-targeted antifolate, is a classical antifolate undergoing intracellular polyglutamation. Polyglutamated MTA is a potent thymidylate synthase (TS) inhibitor and inhibits other folate-dependent enzymes, including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Multifocal antifolates may overcome antifolate resistance, but it is not known whether the anti-tumour activity of MTA depends on its TS inhibition, its primary locus of action, or whether other loci contribute. MTA was examined in three phase I trials using different schedules: a 10-min i.v. infusion given once every 3 weeks, once weekly for 4 weeks every 6 weeks or daily for 5 days every 3 weeks. Dose-limiting toxicities were neutropenia and thrombocytopenia. Other consistently seen side-effects, which were manageable, included mucositis, skin rashes and transient elevations of transaminases. Toxicity was highly schedule dependent: the recommended dose for the 3-weekly schedule (600 mg m(-2)) was 30 times that for the daily x 5 schedule (4 mg m(-2)day(-1)). The 3-weekly dosing schedule was chosen for phase II evaluation. Phase II trials are underway to investigate the activity and toxicity of MTA in several tumour types, including colorectal, pancreas, breast, bladder and non-small-cell lung cancer (NSCLC) Further phase I trials will investigate MTA in combination with other agents, including gemcitabine, cisplatin, 5-fluorouracil and folate. Preliminary phase II trials results are encouraging; responses were seen in colorectal, pancreas, NSCLC and breast cancer.

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Selected References

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  1. Calvert A. H., Alison D. L., Harland S. J., Robinson B. A., Jackman A. L., Jones T. R., Newell D. R., Siddik Z. H., Wiltshaw E., McElwain T. J. A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol. 1986 Aug;4(8):1245–1252. doi: 10.1200/JCO.1986.4.8.1245. [DOI] [PubMed] [Google Scholar]
  2. Calvert A. H., Jones T. R., Dady P. J., Grzelakowska-Sztabert B., Paine R. M., Taylor G. A., Harrap K. R. Quinazoline antifolates with dual biochemical loci of action. Biochemical and biological studies directed towards overcoming methotrexate resistance. Eur J Cancer. 1980 May;16(5):713–722. doi: 10.1016/0014-2964(80)90214-5. [DOI] [PubMed] [Google Scholar]
  3. Crawford J., O'Rourke M., Schiller J. H., Spiridonidis C. H., Yanovich S., Ozer H., Langleben A., Hutchins L., Koletsky A., Clamon G. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol. 1996 Oct;14(10):2774–2784. doi: 10.1200/JCO.1996.14.10.2774. [DOI] [PubMed] [Google Scholar]
  4. Faries D. Practical modifications of the continual reassessment method for phase I cancer clinical trials. J Biopharm Stat. 1994 Jul;4(2):147–164. doi: 10.1080/10543409408835079. [DOI] [PubMed] [Google Scholar]
  5. Gorlick R., Goker E., Trippett T., Waltham M., Banerjee D., Bertino J. R. Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med. 1996 Oct 3;335(14):1041–1048. doi: 10.1056/NEJM199610033351408. [DOI] [PubMed] [Google Scholar]
  6. Jolivet J., Cowan K. H., Curt G. A., Clendeninn N. J., Chabner B. A. The pharmacology and clinical use of methotrexate. N Engl J Med. 1983 Nov 3;309(18):1094–1104. doi: 10.1056/NEJM198311033091805. [DOI] [PubMed] [Google Scholar]
  7. Kris M. G., D'Acquisto R. W., Gralla R. J., Burke M. T., Marks L. D., Fanucchi M. P., Heelan R. T. Phase II trial of trimetrexate in patients with stage III and IV non-small-cell lung cancer. Am J Clin Oncol. 1989 Feb;12(1):24–26. doi: 10.1097/00000421-198902000-00006. [DOI] [PubMed] [Google Scholar]
  8. Lee J. S., Libshitz H. I., Murphy W. K., Jeffries D., Hong W. K. Phase II study of 10-ethyl-10-deaza-aminopterin (10-EdAM; CGP 30 694) for stage IIIB or IV non-small cell lung cancer. Invest New Drugs. 1990 Aug;8(3):299–304. doi: 10.1007/BF00171841. [DOI] [PubMed] [Google Scholar]
  9. O'Connor B. M., Jackman A. L., Crossley P. H., Freemantle S. E., Lunec J., Calvert A. H. Human lymphoblastoid cells with acquired resistance to C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid: a novel folate-based thymidylate synthase inhibitor. Cancer Res. 1992 Mar 1;52(5):1137–1143. [PubMed] [Google Scholar]
  10. Rinaldi D. A., Burris H. A., Dorr F. A., Woodworth J. R., Kuhn J. G., Eckardt J. R., Rodriguez G., Corso S. W., Fields S. M., Langley C. Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol. 1995 Nov;13(11):2842–2850. doi: 10.1200/JCO.1995.13.11.2842. [DOI] [PubMed] [Google Scholar]
  11. Shih C., Chen V. J., Gossett L. S., Gates S. B., MacKellar W. C., Habeck L. L., Shackelford K. A., Mendelsohn L. G., Soose D. J., Patel V. F. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116–1123. [PubMed] [Google Scholar]
  12. Shum K. Y., Kris M. G., Gralla R. J., Burke M. T., Marks L. D., Heelan R. T. Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non-small-cell lung cancer. J Clin Oncol. 1988 Mar;6(3):446–450. doi: 10.1200/JCO.1988.6.3.446. [DOI] [PubMed] [Google Scholar]
  13. Souhami R. L., Rudd R. M., Spiro S. G., Allen R., Lamond P., Harper P. G. Phase II study of Edatrexate in stage III and IV non-small-cell lung cancer. Cancer Chemother Pharmacol. 1992;30(6):465–468. doi: 10.1007/BF00685598. [DOI] [PubMed] [Google Scholar]
  14. Taylor E. C., Kuhnt D., Shih C., Rinzel S. M., Grindey G. B., Barredo J., Jannatipour M., Moran R. G. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem. 1992 Nov 13;35(23):4450–4454. doi: 10.1021/jm00101a023. [DOI] [PubMed] [Google Scholar]
  15. Ward W. H., Kimbell R., Jackman A. L. Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase. Biochem Pharmacol. 1992 May 8;43(9):2029–2031. doi: 10.1016/0006-2952(92)90646-z. [DOI] [PubMed] [Google Scholar]
  16. von Hoff D. D. Human tumor cloning assays: applications in clinical oncology and new antineoplastic agent development. Cancer Metastasis Rev. 1988 Dec;7(4):357–371. doi: 10.1007/BF00051376. [DOI] [PubMed] [Google Scholar]

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